E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Follicular Lymphoma and Diffuse Large B-Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma is a cancer that affects the lymphatic system, a network of vessels and glands spread throughout the body |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012857 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012855 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012856 |
E.1.2 | Term | Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- Phase 1b: Safety and tolerability of the combination of polatuzumab vedotin with bendamustine and rituximab (BR) or bendamustine and obinutuzumab (BG) when administered to patients with relapsed or refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL)
- Phase 1b: Determination of the Recommended Phase II Dose (RP2D) for polatuzumab vedotin given in combination with BR or with BG in patients with R/R FL or DLBCL
- Phase II: Efficacy of the combination of polatuzumab vedotin plus BR compared with BR alone in patients with R/R FL or DLBCL
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E.2.2 | Secondary objectives of the trial |
- Safety and tolerability of the combination of polatuzumab vedotin with BR or BG when administered to patients with R/R FL or DLBCL during the Phase II portion of the study
- Immunogenicity of polatuzumab vedotin and obinutuzumab, as measured by the formation ATAs
- Potential relationships of such anti-therapeutic antibody formation with other outcome measures
- PK of polatuzumab vedotin in combination with BR or BG in patients with R/R FL or DLBCL
- Potential PK interactions between polatuzumab vedotin and BR or BG
- PK exposure response relationship
- Efficacy of the combination of polatuzumab vedotin and BR compared with BR/BG alone as measured by CR, Objective response (OR; CR or PR), CR, OR, and Best objective response (BOR, CR or PR)
- Peripheral neuropathy symptom severity and interference on daily functioning and to better understand treatment impact, tolerability, and reversibility, as measured by the Therapy Induced Neuropathy Assessment Scale (TINAS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Histologically confirmed FL (Grade 1, 2, or 3a) or DLBCL
- Must have received at least one prior therapy for FL or DLBCL. Patients must have either relapsed or have become refractory to a prior regimen as defined in the protocol.
- If the patient has received prior bendamustine, response duration must have been > 1 year (for patients who have relapse disease after a prior regimen)
- At least one bi-dimensionally measurable lesion on imaging scan defined as > 1.5 cm in its longest dimension
- Confirmed availability of archival or freshly collected tumor tissue prior to study enrollment
- Life expectancy of at least 24 weeks
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Adequate hematologic function unless inadequate function is due to underlying disease.
- For women who are not postmenopausal (>=12 months of non−therapy−induced amenorrhea and age >45 years) or surgically sterile: agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period and for >=12 months after the last dose of rituximab or for >=18 months after the last dose of obinutuzumab
- For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing.
- For men, agreement to remain abstinent or to use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of study drug and agreement to refrain from donating sperm during this same period
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E.4 | Principal exclusion criteria |
- History of severe allergic or anaphylactic reactions to humanized or murine MAbs (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
- Contraindication to bendamustine, rituximab, or obinutuzumab
- History of sensitivity to mannitol (mannitol is an excipient in bendamustine)
- Prior use of any MAb, radioimmunoconjugate, or ADC within 5 half-lives or 4 weeks (whichever is longer) of study start before Cycle 1 Day 1
- Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1
- Ongoing corticosteroid use >30 mg/day prednisone or equivalent, for purposes other than lymphoma symptom control
- Completion of autologous stem cell transplant within 100 days prior to Cycle 1 Day 1
- Prior allogeneic stem cell transplant
- Eligibility for autologous SCT (patients with R/R DLBCL)
- Grade 3b follicular lymphoma
- History of transformation of indolent disease to DLBCL
- Primary or secondary CNS lymphoma
- Current Grade >1 peripheral neuropathy
- History of other malignancy that could affect compliance with the protocol or interpretation of results.
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or significant pulmonary disease
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization within 4 weeks prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis,
- Positive test results for chronic hepatitis B virus infection or for hepatitis C virus antibody
- Known infection with HIV or human T-cell leukemia virus 1 virus
- Vaccination with a live vaccine within 28 days prior to treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
- Women who are pregnant or lactating or who intend to become pregnant within a year of the last dose of study treatment in the rituximab cohorts or within 18 months of the last dose of study treatment in the obinutuzumab cohort
- Any abnormal laboratory values as defined in the protocol, unless abnormal laboratory values are due to underlying lymphoma per the investigator
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence, nature and severity of adverse events and serious adverse events
2. Changes in vital signs, physical findings, electrocardiogram, and clinical laboratory results during and following study treatment administration
3. Phase II: Complete Response (CR) at primary response assessment based on positron emission tomography (PET) alone as determined by the Independent Review Committee (IRC)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. Up to 50 months
3. 24 - 32 weeks (6 to 8 weeks after the last dose of study treatment)
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E.5.2 | Secondary end point(s) |
1. CR at primary response assessment based on PET alone, as determined by the investigator
2. CR at primary response assessment based on computed tomography (CT) only, as determined by the investigator and IRC
3. Objective response (OR) as (CR or partial response [PR]) at primary response assessment based on PET alone, as determined by the investigator and IRC
4. OR (CR or PR) at primary response assessment based on CT only, as determined by the investigator and IRC
5. Best objective response (BOR) as (CR or PR) while on study based on PET alone or CT only, as determined by the investigator
6. Formation of anti-therapeutic antibodies (ATAs)
7. Serum and plasma concentrations of polatuzumab vedotin, bendamustine, rituximab, and obinutuzumab versus time
8. PK parameters based on concentration−time data for polatuzumab vedotin, bendamustine, rituximab, and obinutuzumab when these drugs are given in combination
9. Patient Reported Outcomes of peripheral neuropathy symptom severity and symptom interference, as measured by the Therapy-Induced Neuropathy Assessment Scale (TINAS)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. 24 - 32 weeks (6 to 8 weeks after the last dose of study treatment)
6-8. Up to 2 years
9. Up to 3 years
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Phase II randomized for R-containing cohorts but non-randomized for G-containing cohorts |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Polatuzumab vedotin + BR versus BR and polatuzumab vedotin + BG |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Netherlands |
Spain |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the timepoint at which all patients enrolled in the study have had either at least 2 years of follow-up from the time of the Treatment Completion Visit or have discontinued the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |